PEG-Grafted Oligolysines Stabilize DNA Origami While Enhancing Receptor-Specific Cell Binding

DNA nanostructures (DNs) offer programmable platforms
for targeted
biomedical applications, but their limited stability under physiological
conditions has hindered their utility. Protective surface modifiers,
or “coatings”, can improve DN stability but often impede
access of surface-displayed ligands to cell receptors, reducing receptor
engagement and target cell binding. Here, we report polyethylene glycol
(PEG)-grafted oligolysine coatings that simultaneously enhance DN
structural stability and preserve receptor-specific cell binding.
We synthesized a 36-member coating library varying in lysine valency,
PEG molecular weight, and grafting density, and identified three formulations
that bound DNs with ∼ 6-fold higher affinity and conferred
∼ 30-fold greater cargo stability than the widely used K10-b-PEG5k block copolymer. When functionalized
with antibodies, coated DNs selectively engaged Fcγ receptors
on DC2.4 dendritic cellsa phagocytic cell line prone to nonspecific
interactions with uncoated DNsachieving a 12-fold increase
in binding specificity relative to K10-b-PEG5k. Statistical modeling revealed that optimal performance
required coordinated tuning of multiple parameters, underscoring the
importance of multiparametric design. This work identifies improved
protective coatings for DNA origami and establishes a design framework
for engineering biostable, receptor-targeted DNA nanodevices for biological
applications.